New drug development. Preclinical and clinical trials.

Prof. M. Kršiak

Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague

Charles University in Prague, Third Faculty of Medicine

Cycle II, Subject: General Pharmacology Lecture: 18th October 2011

8:00-9:30 Jonas Hall, Ruská 87, Prague

syllabus : http://vyuka.lf3.cuni.cz

1. HISTORY OF DRUG DISCOVERY

2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS

3. STRATEGY, COSTS AND RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS AT PRESENT

4. PHARMACEUTICAL COMPANIES

5. DRUG REGULATORY AGENCIES

6. SUMMARY

1. HISTORY OF DRUG DISCOVERY

Drugs/medicines of plant origin

poppy - opium

willow – bark Hippokrates 400 p.n.l.

1829 – salicin >

1853 sodium salicylate >

1899 acetylsalicylic acid ASPIRIN

ADVANCES IN CHEMISTRY

Felix Hoffmann

ASPIRIN Bayer

1899

1905 FIRST CZECH TEXTBOOK OF PHARMACOLOGY

1905 there was:

aspirin, digitalis, ether, cocaine, bromide, saccharin

1905 did not exist:

drugs e.g. For hypertension, diabetes, asthma, antibacterial drugs, lipid-lowering drugs, psychotropic drugs emika, etc

1905 ignorance of

neurotransmitters molecular targets of drug

+ Advances in pharmacology

1963 propranolol – betablockers – hypertension, angina pectoris

1972 cimetidin – H2 antagonists – peptic ulcer disease

Sir James W. Black

Nobel price 1988

GREAT SUCCESSES

…BUT REGRETTABLY…

DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE

DRUGS CAN CAUSE DISASTERS

THALIDOMIDE 1956 – 1961 about 10 000 children affected,

not in USA [FDA]

2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW

DRUGS

- BEFORE DRUGS CAN BE APPROVED FOR USE

- AFTER DRUGS ARE APPROVED FOR USE

SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS

PRECLINICAL DEVELOPMENT

CLINICAL TRIALS

REGISTRATION

POSTMARKETING

SURVEILLANCE

SAFETY -PHARMACOVIGILANCE

PRE-CLINICAL DEVELOPMENT

EVALUATION

• PHARMACOLOGICAL (pharmacodynamics, pharmacokinetics)

• TOXICOLOGICAL (toxicity acute, chronic, special toxicity tests e.g. – embryotoxicity,teratogenity, mutagenity, cancerogenity

• PHARMACEUTICAL (e.g. identity, formulation, stability)

GOOD LABORATORY PRACTICE - GLP

CLINICAL TRIALS

GCP (Good Clinical Practice)

selection of probands, randomization, control group, double-blind experiment, randomized controlled trials (RCT), placebo, bias, informed consent, Declaration of Helsinski, ethical committees …

PHASES

I. healthy volunteers a small (20-100) group – first evaluation of tolerability, kinetics

II. first patients larger groups (100-300) - first evaluation of therapeutic efficacy

III. randomized controlled multicenter trials on large patient groups (300–3,000 or more) - the definitive assessment of how effective the drug is

IV. Postmarketing surveillance after drug receives permission to be sold - the safety surveillance

CLINICAL TRIALS - cont

NEW DRUGS

NOVEL TYPE OF ACTION

NEW CHEMICAL/ MOLECULAR ENTITY (NCE/NME)

„MEE-TOO“

GENERICS (actually copies of the original drug once the patent expires)

3. STRATEGY IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS

Known type of action, but NCE/NME[additional betablockers, H2 antagonists, PPIs, statins, triptans etc…]

first betablocker, H2 antagonist, PPI, statin, triptan …

bioequivalence

„Blockbuster“

3. RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS -NME

Preziosi 2004

3. COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME

NEW DRUGS

NOVEL TYPE OF ACTION

NEW CHEMICAL/ MOLECULAR ENTITY (NCE/NME)

„MEE-TOO“

GENERICS (actually copies of the original drug once the patent expires)

3. STRATEGY IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS

Known type of action, but NCE/NME[additional betablockers, H2 antagonists, PPIs, statins, triptans etc…]

first betablocker, H2 antagonist, PPI, statin, triptan …

bioequivalence

„Blockbuster“

4. PHARMACEUTICAL COMPANIES

Pfizer, AstraZeneca, Eli Lilly, Merck, Novartis, Abbot, GlaxoSmithKline, Bristol-Myers, Sanofi-Synthelabo, Janssen-Cilag, etc.

1951 -1990 (1999)VÝZKUMNÝ ÚSTAV PRO FARMACII

A BIOCHEMII (VÚFB)

AJATIN liq., tct.DITHIADEN tbl., inj.VALETOL tbl PROTHIADEN tbl.MESOCAIN inj., gel.TRIMEPRANOL tbl., inj.KINEDRYLaj., aj.

New drug discovery and development in Czech republic - history

MEE-TOO DRUGS

PROTHIADEN

(dosulepin)

Domestic (SPOFA)

Exported (Boots)

1968-1994 0,5 bilions Kčs

23 bilions Kčs

Dr. M. Protiva, DrSc.prof.MUDr. Z. Votava, DrSc.

RNDr. PhMr. J. Metyšová,CSc.

VÚFB

antidepressant

TRIMEPRANOL

(metipranolol)

Domestic (SPOFA)

Exported (Boehringer-Ingelheim)

1971-1993 1.460 bilions Kčs

11.2 bil. Kčs

Doc. MUDr. Václav TRČKA, DrSc.

VÚFB

betablocker

NCE/NME

Antivirals

New drug discovery and development in Czech republic

- at present

ZENTIVA Good Manufacturing Practice

GENERICS

Prof. RNDr. Antonín Holý, DrSc., Dr.h.c.Institute of Organic Chemistry and BiochemistryAcademy of the Sciences of the Czech Republic Prague

5. DRUG REGULATORY AGENCIES

EUROPEAN MEDICINES AGENCY (EMEA)

Committee for Medicinal Products for Human Use (CHMP)

Státní ústav pro kontrolu léčiv (SÚKL)

Medicines and Healthcare products Regulatory Agency

Bundesinstitut für Arzneimittel und Medizinprodukte

FOOD AND DRUG ADMINISTRATION (FDA)

→

www.ema.europa.eu

6. SUMMARY

• DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE

• DISCOVERY AND DEVELOPMENT OF NEW DRUGS IS DIFFICULT, COSTY AND RISKY

•A SOFISTICATED SYSTEM FOR EVALUATION OF EFFICACY AND SAFETY OF DRUGS HAS BEEN DEVELOPED